1. Field of the Invention
The present invention relates generally to methods and compositions for facilitating the therapeutic or diagnostic administration of exogenous macromolecules to vertebrate hosts. In particular, it relates to methods and compositions for the extracorporeal removal of endogenous antibody elicited by human patients in response to treatment or diagnosis with exogenous antibodies.
Various immunotherapeutic strategies have been developed to mimic or bolster a patient's own immune response in fighting a disease or infection. In general, such immunotherapeutic strategies involve the administration of exogenous (non-human) antibody to the patient which are intended to react with a particular remainder of the cells unaffected. Usually, the antibody will be attached to a lethal agent, such as a drug, radioactive isotope, or a toxin, which will result in killing the cells without reliance on the patient's own humoral response mechanism. Alternatively, non-conjugated antibodies can be used with reliance on the patient's own immune system to kill the desired cells. The use of antibody conjugated to lethal agents, generally referred to as immunotoxins, has offered great hope in the treatment of cancers where the antibodies may be directed at tumor markers which differentiate the cancer cells from normal body cells.
Despite certain initial successes in cancer therapy, consistent effective treatments have not yet been achieved. One particular problem has been that the patient's immune system recognizes the exogenous antibodies as "foreign." Thus, initial treatments with the immunotoxins will sensitize the patient and subsequent treatments can evoke increasingly strong immune responses which can interfere with the effectiveness of the therapy. As it will usually be desirable to continue the therapy over relatively long periods of time, the immune response has proven to be a major impediment to effective treatment.
Various diagnostic strategies using radiolabeled antibodies have been developed to determine the size and position of various tissues within a patient's body. These diagnostic modalities include locating metastatic tumor foci, determining the size of heart tissue, evaluating vascular abnormalities, etc. These techniques have also been associated with the problem of the patient's endogenous immune reaction to the diagnostic macromolecules. As it will usually be desirable to repeat, at various times, the diagnostic procedure over relatively long periods, the immune response will be a major impediment to effective diagnosis.
It would thus be desirable to provide methods and compositions which will inhibit or minimize the patient's immune response to the administration of exogenous antibodies or other macromolecules. In particular, it would be desirable if such methods would allow the repeated administration of exogenous antibodies or macromolecules to an individual patient over extended periods of time, preferably indefinitely.
2. Description of the Background Art
Specific removal of circulating antibody by extracorporeal immunoadsorption employing specifically immobilized antigen has been described by various investigators. Specific removal of antibody from blood employing hemoperfusion through a porous gel was originally described by Schenkein et al. (1971) J. Clin. Invest. 50:1864. Terman and co-workers subsequently described techniques employing collodion-charcoal in which circulating antibody in animal plasma could be removed in an extracorporeal system as described in Clin. Exp. Immunol. (1976) 24:231 and Clin. Exp. Immunol. (1977) 28:180. This technique was successfully applied by Terman and co-workers to treat a patient with systemic lupus erythematosus as described in Lancet (1979) 2:824. However, it was later demonstrated by Balint et al., Cancer Res. (1984) 44:734, that such absorbents may leak the immobilized protein upon contact with blood plasma. Such leakage can cause further hyperimmunization of the host after the immunoadsorption procedure. Blood treatment systems for the removal of anti-A and anti-B antibodies are described by Bensinger et al. in a technique which utilizes synthetic human blood group antigens covalently linked to a silica matrix as described in N. Engl. J. Med. (1981) 304:160. The preparation and use of immunotoxins in the treatment of cancer and other diseases is taught in U.S. Pat. Nos. 4,340,535; 4,590,071; and 4,671,958. The extracorporeal removal of patient antibody produced in response to treatment with exogenous antibody has not been previously described. A system for the extracorporeal adsorption of IgG and circulating immune complexes using a protein A column is described in U.S. Pat. No. 4,681,870.